G. I. Hockings

Naloxone-Induced Acth Release in Man Is Inhibited by Clonidine

1. Adrenergic mechanisms play an important role in regulation of ACTH release. We used the α2‐adrenergic agonist, clonidine, as a central nervous system inhibitor of ACTH release to see if it would alter naloxone‐induced ACTH secretion in normal human volunteers.

Naloxone-induced ACTH release: mechanism of action in humans.

Our understanding of the neuroendocrine control of ACTH secretion has undergone rapid advances since the discovery of corticotrophin-releasing hormone (CRH) in 198 1 (Orth, 1992). This 41-amino acid peptide is stored together with vasopressin in some or all of the parvicellular neurones of the paraventricular nucleus of the hypothalamus and different stimuli cause varying amounts of these two peptides to be released into the hypophyseal portal circulation (Inder et al., 1995). In humans and other species, CRH and vasopressin act synergistically to cause ACTH release from anterior pituitary corticotropes @e Bold et al., 1984). Other putative ACTH secretagogues such as angiotensin 11, adrenaline and noradrenaline have no effect on ovine CRH-induced ACTH release in humans (Orth, 1992). Thus, the principal ACTH secretagogues in humans are CRK and arginine vasopressin (AVP). The opioid antagonist naloxone was first reported to increase plasma ACTH and cortisol in humans in 1979 (Volavka et al., 1979). It was finally realized that doses of naloxone in the 10-20mg range, an order of magnitude higher than standard clinical doses, were required to cause cortisol release in man (Morley et al., 1980; Grossman & Besser, 1982). Significant increases in both ACTH and cortisol after naloxone administration to humans have been reported in randomized, double-blind, placebo-controlled studies (Al-Damluji et al., 1990; Torpy et al., 1993). In both of these studies, and in all other studies where ACTH and cortisol were both measured, ACTH rose first and peaked about 15 minutes prior to the cortisol peak, suggesting that naloxone causes cortisol secretion by releasing ACTH. Naloxone induced ACTH release in humans is blocked by pretreatment with the a ] -adrenergic antagonist, thymoxamine (Grossman & Besser, 1982), and the al-adrenergic agonist,

Hypersensitivity of the hypothalamic-pituitary-adrenal axis to naloxone in post-traumatic stress disorder

Naloxone, which increases endogenous corticotropin-releasing hormone (CRH) release by blocking an inhibitory opioidergic tone on the hypothalamic-pituitary-adrenal (HPA) axis, was administered in a dose-response protocol to seven healthy volunteers and 13 patients with treated posttraumatic stress disorder (PTSD). Six of the PTSD patients showed an increased hormonal response to the lowest naloxone dose (6 micrograms/kg) compared to both the control subjects and the other PTSD patients. This difference persisted on detailed subgroup analysis, although it was less marked at the highest naloxone dose (125 micrograms/kg). The responses of the other seven PTSD patients were indistinguishable from those of the control group. The greater responses of the six PTSD patients could not be explained on the basis of associated psychiatric illnesses or psychotropic drug therapy, and did not correlate with standard psychological testing or severity of PTSD. The results of this preliminary study therefore suggest that a hypersensitivity of the HPA axis to endogenous CRH stimulation may occur in PTSD.

A Synergistic Adrenocorticotropin Response to Naloxone and Vasopressin in Normal Humans - Evidence That Naloxone Stimulates Endogenous Corticotropin-Releasing Hormone

Naloxone stimulates pituitary-adrenal function by blocking an endogenous inhibitory opioidergic tone which modulates pituitary adrenocorticotropin (ACTH) release. In animals, this action of naloxone is mediated by increased corticotropin-releasing hormone (CRH) secretion, but such a mechanism is disputed in humans. CRH and arginine vasopressin (AVP) are known to have a synergistic effect on ACTH secretion in both humans and animals. In vitro, this synergism is independent of L-type voltage-dependent Ca2+ channel function. The aims of this study were therefore: (i) to determine if the combined administration of naloxone and AVP is synergistic regarding ACTH release; (ii) to assess the effect of nifedipine, which blocks L-type Ca2+ channels, on the ACTH response to combined naloxone/AVP stimulation. Seven healthy volunteers were studied using a placebo-controlled, single-blind protocol. Naloxone (125 micrograms/kg) and/or AVP (10 units) were given in all four possible combinations, and oral nifedipine (20 mg) was also given with naloxone and AVP as an additional test. The mean AUC and the mean peak change in ACTH levels following combined naloxone/AVP administration were both significantly greater than the arithmetic sum of the ACTH responses to naloxone and AVP given on separate occasions (AUC: 1,576.4 +/- 417.9 vs. 567.1 +/- 106.1 pmol.min.l-1, p < 0.002; peak change: 37.9 +/- 14.0 vs. 11.8 +/- 2.0 pmol/l, p < 0.007). Nifedipine reduced the ACTH response to combined naloxone/AVP stimulation by 43% (AUC: 1,576.4 +/- 417.9 vs. 897.0 +/- 186.2; p < 0.05), but it remained greater than the sum of the individual responses (897.0 +/- 186.2 vs. 576.1 +/- 106.1, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The Insulin Hypoglycemia Test: Hypoglycemic Criteria and Reproducibility

The insulin hypoglycemia test (IHT) is widely regarded as the ‘gold standard’ for dynamic stimulation of the hypothalamic‐pituitary‐adrenal (HPA) axis. This study aimed to investigate the temporal relationship between a rapid decrease in plasma glucose and the corresponding rise in plasma adenocorticotropic hormone (ACTH), and to assess the reproducibility of hormone responses to hypoglycemia in normal humans. Ten normal subjects underwent IHTs, using an insulin dose of 0.15 U/kg. Of these, eight had a second IHT (IHT2) and three went on to a third test (IHT3). Plasma ACTH and cortisol were measured at 15‐min intervals and, additionally, in four IHT2s and the three IHT3s, ACTH was measured at 2.5‐ or 5‐min intervals. Mean glucose nadirs and mean ACTH and cortisol responses were not significantly different between IHT1, IHT2 and IHT3. Combined data from all 21 tests showed the magnitude of the cortisol responses, but not the ACTH responses, correlated significantly with the depth and duration of hypoglycemia. All subjects achieved glucose concentrations of of ≤ 1.6 mmol/l before any detectable rise in ACTH occurred. In the seven tests performed with frequent sampling, an ACTH rise never preceeded the glucose nadir, but occurred at the nadir, or up to 15 min after. On repeat testing, peak ACTH levels varied markedly within individuals, whereas peak cortisol levels were more reproducible (mean coefficient of variation 7%). In conclusion, hypoglycemia of ≤ 1.6 mmol/l was sufficient to cause stimulation of the HPA axis in all 21 IHTs conducted in normal subjects. Nonetheless, our data cannot reveal whether higher glucose nadirs would stimulate increased HPA axis activity in all subjects. Overall, the cortisol response to hypoglycemia is more reproducible than the ACTH response but, in an individual subject, the difference in peak cortisol between two IHTs may exceed 100 nmol/l.

NALOXONE STIMULATION OF ACTH SECRETION DURING PETROSAL SINUS SAMPLING IN CUSHING'S SYNDROME

1. Petrosal sinus sampling has been used to establish the source of adrenocorticotropin (ACTH) in ACTH‐dependent Cushings syndrome. Naloxone, an opioid antagonist, stimulates ACTH secretion, probably via release of endogenous hypothalamic corticotropin releasing hormone (CRH).

NEW DIAGNOSTIC TESTS FOR CUSHING'S SYNDROME: USES OF NALOXONE, VASOPRESSIN AND ALPRAZOLAM

1. We set out to investigate whether the administration of naloxone alone, naloxone plus vasopressin (AVP) or naloxone plus alprazolam to patients with Cushings syndrome would result in a blunted dynamic response of the pituitary‐adrenal axis compared with normal volunteers. Cushings syndrome is often difficult to diagnose. It would be helpful if new tests were available to help in the biochemical distinction between Cushings syndrome and non‐Cushings syndrome patients.

L-Type Calcium Channels and Crh-Mediated Acth and Cortisol Release in Humans

1. The effect of pretreatment with nifedipine on naloxone‐stimulated corticotrophin‐releasing hormone (CRH)‐induced adrenocorticotrophin (ACTH) release in humans was investigated. The mean peak plasma ACTH and cortisol levels and the mean peak change in cortisol levels from basal were significantly lower in the nifedipine/naloxone test than in the naloxone alone test. The integrated areas under the ACTH‐time and cortisol‐time curves were reduced by 33 and 49%, respectively, in the nifedipine/naloxone test compared with the naloxone alone test. These results correlate well with published in vitro studies.

Early rise in blood pressure following administration of adrenocorticotropic hormone-[1-24] in humans

1. An elevation in blood pressure has been consistently observed 24 h after adrenocorticotropic hormone (ACTH) administration and is caused by increased ACTH‐stimulated cortisol secretion, in association with increased cardiac output. The aim of the present study was to investigate the previously undefined time of onset of this increase in blood pressure in normal humans.

The use of naloxone for investigating disorders of the hypothalamic-pituitary-adrenal axis

The hypothalamic-pituitary-adrenal (HPA) axis forms an integral and vital part of the stress response system. Pituitary ACTH secretion is regulated by two hypothalamic peptides, corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), with CRH being the primary mediator in humans. Numerous neuronal circuits within the brain influence the activity of the CRH neurons in the paraventricular nuclei of the hypothalamus, including endogenous opioid systems. Opioid receptors are widely distributed in the brain but have a particular association with three major neural networks: the sensory, limbic and neuroendocrine systems. Opioidergic agents affect HPA activity in humans and animals, al though important species differences exist. In vitro and in vivo studies provide considerable evidence for a centrally mediated effect of opioidergic agents on the HPA axis, most likely by direct action on the hypothalamus. Naloxone is a competitive antagonist at multiple opioid receptor subtypes. Clinical investigations utilizing naloxone administration in humans have had three primary aims:1) to elucidate the role of endogenous opioid systems in the normal physiology of the HPA axis; 2) to study the pathophysiology of disorders associated with or caused by dysfunction of the HPA axis; 3) to develop new diagnostic tests. High doses of naloxone stimulate the human HPA ards causing rises in plasma ACTH and cortisol concentrations. Pharmacological stud ies strongly suggest that naloxone blocks a tonic inhibitory effect of endogenous opioids on central alpha-adrenergic pathways, which in turn stimulate ACTH secretion via CRH release from the hypothalamus. Therefore, the naloxone test provides a means of evaluating hypothalamic CRH reserve and assesses the integrity of the entire HPA axis. Several disorders are associated with dysregulation of the HPA axis including major depression, post-traumatic stress disorder, alcoholism, chronic fatigue syndrome, Cushings syndrome, and obesity. Major depression is a condition often associated with clinical and biochemical evidence of hypercortisolism (pseudo-Cushings syndrome) and may be very difficult to distinguish from patients with true Cushings syndrome. Patients with pseudo-Cushings syndrome are postulated to have hypersecretion of hypothalamic CRH producing an upregulation of an otherwise normal HPA axis. Patients with major depression have an ACTH hyperresponse to naloxone compared with healthy subjects and patients with Cushings disease. This increased ACTH response is further exaggerated by combining naloxone administration with the direct corticotrope stimulation provided by exogenous AVP. The naloxone test also has potential diagnostic utility-when central adrenal insufficiency is suspected. Naloxone applies a specific pharmacological stimulus at the hypothalamic level, therefore a normal ACTH and cortisol response implies functional integrity of all three components of the HPA axis. Preliminary studies comparing naloxone administration with the insulin hypoglycemia and metyrapone tests are promising. The naloxone test may provide an alternative in patients with suspected central adrenal insufficiency who are unable to undergo an insulin hypoglycemia test or a metyrapone test because of safety issues.